Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

• a CPA to be used as an organocatalyst or to a phosphoramidite to be used as a chiral ligand. Testing these new structures on known stereoselective transformations, the authors achieved high yields and enantioselectivities (up to 98% yield and 97% ee). Wang et al. performed asymmetric (4 + 3

Synthesis of 1,4-azaphosphinine nucleosides and evaluation as inhibitors of human cytidine deaminase and APOBEC3A

• Maksim V. Kvach,
• Stefan Harjes,
• Harikrishnan M. Kurup,
• Geoffrey B. Jameson,
• Elena Harjes and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2024, 20, 1088–1098, doi:10.3762/bjoc.20.96

• medium). Then, the α- or β-anomer of salt 21 was converted to 2-cyanoethoxy derivative 22 using 3-hydroxypropionitrile and TBTU. This was further transformed into the required phosphoramidite 23 as individual α- or β-anomer, which was used in the preparation of modified DNA sequences on a DNA synthesiser

• -protected phosphoramidite of nucleoside Va and the incorporation into DNA was more straightforward, but no inhibition of A3A was observed for these ODNs. These results suggest that negatively charged nucleobases cannot be accommodated in the active site of hCDA and A3A, and other options need to be

Long oligodeoxynucleotides: chemical synthesis, isolation via catching-by-polymerization, verification via sequencing, and gene expression demonstration

• Yipeng Yin,
• Reed Arneson,
• Alexander Apostle,
• Adikari M. D. N. Eriyagama,
• Komal Chillar,
• Emma Burke,
• Martina Jahfetson,
• Yinan Yuan and
• Shiyue Fang

Beilstein J. Org. Chem. 2023, 19, 1957–1965, doi:10.3762/bjoc.19.146

• ODN sequences are provided in Supporting Information File 1) GFP gene construct was divided into a 399 and 401 nt ODNs for automated synthesis (step 1, Figure 1). The syntheses were carried out in commercial 0.2 µmol 2000 Å CPG columns on an ABI 394 DNA/RNA synthesizer using phosphoramidite chemistry

• caused by long ODNs, the loading of the synthesis column was reduced from 0.2 µmol to 0.1 µmol. This was achieved by applying a solution containing 0.05 M 5'-DMTr-dT-phosphoramidite (1a, Scheme 1) and 0.05 M 5'-Bz-dT-phosphoramidite (1b) for the coupling step in the first synthetic cycle. Because the Bz

• cycle, the polymerizable tagging phosphoramidite 2, of which the synthesis was described earlier [20] (Scheme 1), was used in the coupling step, and the reaction was repeated three times for 5 minutes each time to maximize the yield of tagging the full-length sequences with the polymerizable

Synthesis of ether lipids: natural compounds and analogues

• Marco Antônio G. B. Gomes,
• Alicia Bauduin,
• Chloé Le Roux,
• Romain Fouinneteau,
• Wilfried Berthe,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96

• method was developed for the incorporation of the phosphocholine polar head group that makes use of the phosphoramidite 8.2 which is a weakly air sensitive reagent [85]. This method was applied for the synthesis of PAF as illustrated in Figure 8 [86]. The alcohol 8.1 reacted with 8.2 in the presence of

• ) produced 20.4. Then, the incorporation of the phosphoinositol moiety was achieved by using phosphoramidite chemistry. First, the alcohol 20.4 reacted with O-benzyl-N,N,N’,N’-tetraisopropylphosphorodiamidite to produce the phosphoramidite 20.5 that subsequently reacted with dibenzyl-tris(dibenzylphosphate

Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

• (phosphite/phosphine-pyridine amide, phosphine-sulfoxide, phosphoramidite, MINBOL, see Figure 1) and they usually showed excellent diastereoselectivity (dr >20:1). The catalytic systems even with low catalyst loadings tolerated both electron-donating and withdrawing groups on the aromatic substituents

• the trapping of metal enolates by Michael reactions with nitroalkenes 122 and disulfonyl ethylenes 124 (Scheme 31) [67]. The conjugate additions of dialkylzinc, Grignard, and trialkylaluminum reagents to cyclic enones 121 were realized using previously established chiral phosphoramidite, carbene or

• in the first step by the phosphoramidite ligand L39 (92% ee, dr 1:1) (Scheme 60). Recently, Liu and co-workers reported the stereoselective synthesis of the tricyclic core of dodecahydrodibenzo[b,d]furan skeleton containing 12-epi-JBIR-23 and -24 [111]. Besides their intriguing complex structures

Heteroleptic metallosupramolecular aggregates/complexation for supramolecular catalysis

• Prodip Howlader and
• Michael Schmittel

Beilstein J. Org. Chem. 2022, 18, 597–630, doi:10.3762/bjoc.18.62

• demonstrated by Reek and co-workers by using a previously reported heteroleptic bisporphyrin cage [76]. The tetragonal prismatic nanocage 47 consisted of two zinc-porphyrin units along the two tetragonal faces (Figure 11), which allowed encapsulation of the chiral phosphoramidite 48 as a precursor for the

The role of chemistry in the success of oligonucleotides as therapeutics

• Pawan Kumar and
• Tom Brown

Beilstein J. Org. Chem. 2022, 18, 197–199, doi:10.3762/bjoc.18.22

• quantities of oligonucleotides it would not have been possible to develop them as therapeutic agents. Forty years ago, the synthesis of an oligonucleotide in the lab was a huge task. Since then, seminal work from the Caruthers lab has solved this problem with the introduction of phosphoramidite chemistry [4

• ]. This proved an outstanding breakthrough and is currently catalyzing the development of many new technologies including next generation siRNAs, antisense oligonucleotides, and CRISPR-based gene editing systems. Thanks to this phosphoramidite approach, it has also been possible to mass-produce

Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides

• Mathias B. Danielsen and
• Jesper Wengel

Beilstein J. Org. Chem. 2021, 17, 1828–1848, doi:10.3762/bjoc.17.125

• between the modified nucleobase and the corresponding guanidine, which resulted in an increase in Tm of 16 °C, i.e., in the same range as obtained with the original G-clamp (Table 3A) [59]. Generally, conversions of nucleoside phosphoramidite synthons have been explored only rarely. However, the

• commercially available 3’-phosphoramidite derivative of 5’-O-dimethoxytrityl-2’-O-methyluridine could be converted into an N4-triazole-modified 2’-OMe-cytidine phosphoramidite [60]. This concept was later used to prepare spermine-functionalized 2’-OMe and 2’-O-((2-methoxy)ethyl) (MOE)cytidine phosphoramidites

• be taken when conjugating amine moieties onto guanine. Interestingly, in a post-oligo synthetic modification approach, a 2-fluoro-6-p-nitrophenylethyl-2’-deoxyinosine-3'-phosphoramidite monomer was incorporated twice into an 11-mer ON, whereupon spermine was attached to the 2-position of the purine

Double-headed nucleosides: Synthesis and applications

• Vineet Verma,
• Jyotirmoy Maity,
• Vipin K. Maikhuri,
• Ritika Sharma,
• Himal K. Ganguly and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2021, 17, 1392–1439, doi:10.3762/bjoc.17.98

• double-headed nucleosides 4a,b were dimethoxytritylated (DMTr), phosphitylated, and incorporated into DNA oligonucleotides using the standard automated phosphoramidite method. The UV-based melting temperature (Tm) of hybrids of the modified oligonucleotides with complementary DNA strands were studied

• nucleoside 37 (Scheme 9) [34]. The double-headed nucleoside 37 was dimethoxytritylated, phosphitylated, and incorporated into 11- to 13-mer oligonucleotides using the standard automated phosphoramidite method. The UV-based melting temperature (Tm) of hybrids of the modified oligonucleotides with

• nucleoside monomers 125a–c were incorporated into oligodeoxyribonucleotides via phosphoramidite derivatization of the C-3′ hydroxy group present in the moiety. The oligonucleotides thus synthesized were found to stabilize the duplex formed with complementary DNA [69]. Nielsen and co-workers [43][70

Recent advances in palladium-catalysed asymmetric 1,4–additions of arylboronic acids to conjugated enones and chromones

• Jan Bartáček,
• Jan Svoboda,
• Martin Kocúrik,
• Jaroslav Pochobradský,
• Alexander Čegan,
• Miloš Sedlák and
• Jiří Váňa

Beilstein J. Org. Chem. 2021, 17, 1048–1085, doi:10.3762/bjoc.17.84

• the reaction (Scheme 6) [40]. A different approach using microwave irradiation was explored by the group of Toma et al. [41]. After an initial tuning of the reaction conditions of a catalytic system based on Pd(OAc)2/2,2’-bipy several optically pure phosphoramidite and diphosphine ligands in

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

• Christopher Liczner,
• Kieran Duke,
• Gabrielle Juneau,
• Martin Egli and
• Christopher J. Wilds

Beilstein J. Org. Chem. 2021, 17, 908–931, doi:10.3762/bjoc.17.76

• synthesize the nucleoside dimer phosphoramidite with the appropriate amide linkage, which can then be introduced into the strand by solid-phase synthesis. These dimers are synthesized by using an amide coupling reagent to condense a 3'-carboxylic acid nucleoside with a 5'-amine nucleoside, where the

• obtained through condensation with N,N-dicyclohexylcarbodiimide (DCC) giving rise to homopolymeric tetramers of either G-GNA or T-GNA [97]. In 1996, Acevedo and Andrews were the first to demonstrate the synthesis of GNA nucleoside phosphoramidite derivatives as well as the ability of the phosphoramidite

• -di-O-benzoyl-2-deoxy-2-fluoro-α-ᴅ-arabinofuranosyl bromide (Scheme 7) [176][177][178][179][180]. Both β-ᴅ-arabino and 2'-fluoro-β-ᴅ-arabinofuranose nucleosides can be converted to phosphoramidite derivatives for incorporation into oligonucleotides for solid-phase synthesis [178][181][182][183][184

DNA with zwitterionic and negatively charged phosphate modifications: Formation of DNA triplexes, duplexes and cell uptake studies

• Yongdong Su,
• Maitsetseg Bayarjargal,
• Tracy K. Hale and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2021, 17, 749–761, doi:10.3762/bjoc.17.65

• -phase DNA or RNA synthesis, the introduction of SaRNA monomers into an RNA backbone involved a 14-step preparation of the phosphoramidite for the SaRNA-TT dinucleotide. Similarly, the incorporation of BCNS groups on a DNA backbone requires the synthesis of thymidine and 2’-OMe-uridine phosphoramidites

Synthesis and properties of oligonucleotides modified with an N-methylguanidine-bridged nucleic acid (GuNA[Me]) bearing adenine, guanine, or 5-methylcytosine nucleobases

• Naohiro Horie,
• Takao Yamaguchi,
• Shinji Kumagai and
• Satoshi Obika

Beilstein J. Org. Chem. 2021, 17, 622–629, doi:10.3762/bjoc.17.54

• for the guanidine moiety because it can be easily removed under the basic conditions (ammonia/methylamine solution) used for the DNA synthesis [20]. The phosphoramidite synthesis was started from 2'-amino-LNAs 1a–c, which were rapidly prepared via the transglycosylations of 2'-amino-LNA-T [25]. First

• modified with GuNA[Me]-A, -G, or -mC (0.2 µmol scale) was performed using the nS-8 oligonucleotide synthesizer (GeneDesign, Inc.) according to the standard phosphoramidite protocol with 0.5 M 5-ethylthiotetrazole as an activator. The protocol is similar to that described in reference [20]. A Custom Primer

Incorporation of a metal-mediated base pair into an ATP aptamer – using silver(I) ions to modulate aptamer function

• Marius H. Heddinga and
• Jens Müller

Beilstein J. Org. Chem. 2020, 16, 2870–2879, doi:10.3762/bjoc.16.236

• phosphoramidite-protected imidazole nucleoside as required for automated DNA solid-phase synthesis was synthesized as previously reported [30]. The oligonucleotides were synthesized on a DNA/RNA synthesizer H-8 (K&A Laborgeräte) using standard protocols for automated solid-phase synthesis (coupling time: 1000 s

• for unnatural nucleosides). All natural nucleosides (A, T, G, and C), the fluorescein phosphoramidite as well as the DABCYL-CPGs were obtained from Glen Research. The oligonucleotides were deprotected and cleaved from the support by incubation in AMA solution (1:1, 40% methylamine and aqueous ammonia

Changed reactivity of secondary hydroxy groups in C8-modified adenosine – lessons learned from silylation

• Jennifer Frommer and
• Sabine Müller

Beilstein J. Org. Chem. 2020, 16, 2854–2861, doi:10.3762/bjoc.16.234

• , functionalized phosphoramidite building blocks of all four nucleosides are highly desired. The number of commercially available RNA phosphoramidites that carry a suitable functionality for post-synthetic attachment of dyes, reporter groups or other conjugates is still rather limited. In particular, monomer

• synthesized a number of pyrimidine and purine derivatives carrying amino linkers of different length and flexibility [13][20]. Linker-modified uridine derivatives, upon conversion into phosphoramidite building blocks, were incorporated in RNA and used for a systematic study of distance determination of

• phosphoramidite building block 9 (Scheme 2). Results and Discussion Typically, the synthesis of C8-alkynyl derivatives relies on C8-bromoadenosine as reactant for the Sonogashira cross-coupling reaction to introduce the amino linker N-(propyn-2-yl)-6-(trifluoroacetamido)hexanamide (L) bearing an alkynyl moiety

Nonenzymatic synthesis of anomerically pure, mannosyl-based molecular probes for scramblase identification studies

• Giovanni Picca,
• Markus Probst,
• Simon M. Langenegger,
• Oleg Khorev,
• Peter Bütikofer,
• Anant K. Menon and
• Robert Häner

Beilstein J. Org. Chem. 2020, 16, 1732–1739, doi:10.3762/bjoc.16.145

• citronellol derivative via a phosphodiester bridge. Moreover, a novel phosphoramidite chemistry-based method offers a straightforward approach for the non-enzymatic incorporation of the saccharide moiety in an anomerically pure form. Keywords: carbohydrates; citronellol; phosphoramidite; photoclickable

• into stereodefined, anomeric phosphoramidite derivatives. The method is based on adapted procedures developed for DNA solid-phase synthesis [17]. Phosphoramidite chemistry allows the connection of two molecular entities via a phosphodiester linkage and was found to be perfectly suited for this purpose

• . Reports of using phosphoramidite chemistry for the preparation of carbohydrates via the anomeric position are relatively rare [18][19][20][21][22][23]. Alternatively, the H-phosphonate approach has been used to convert carbohydrates into phosphate-linked derivatives at the anomeric center [24][25][26][27

Copper-catalysed alkylation of heterocyclic acceptors with organometallic reagents

• Yafei Guo and
• Syuzanna R. Harutyunyan

Beilstein J. Org. Chem. 2020, 16, 1006–1021, doi:10.3762/bjoc.16.90

• copper-catalysed asymmetric conjugate addition (ACA) of dialkylzinc reagents to N-substituted 2,3-dehydro-4-piperidones 1 in order to access useful chiral piperidine derivatives (Scheme 1A) [15]. They found the catalytic system based on the chiral phosphoramidite L1 and a copper salt to be the most

• an N-acyl-4-methoxypyridinium salt using a copper/phosphoramidite catalytic system (Scheme 3) [20][21]. The authors highlighted that the N-acylpyridinium salts were unstable species and that their instability affected the regioselectivity of the dearomatisation process upon the nucleophilic addition

• acceptors with trialkylaluminium reagents was explored by the group of Alexakis in 2009 (Scheme 11) [41]. Various chiral phosphoramidite ligands, in combination with a copper salt, were found to be efficient catalysts for this transformation, with the best results obtained with the ligand L16. Feringa and

Recent advances in Cu-catalyzed C(sp³)–Si and C(sp³)–B bond formation

• Balaram S. Takale,
• Ruchita R. Thakore,
• Elham Etemadi-Davan and
• Bruce H. Lipshutz

Beilstein J. Org. Chem. 2020, 16, 691–737, doi:10.3762/bjoc.16.67

• alcohols (Scheme 44) [82]. In most cases, high chemical yields along with high ees were obtained when phosphoramidite ligand L28 was used. A wide variety of compounds was prepared, including one with a bisquarternary center (267), although the Bpin residue within it could not be oxidized to the desired

Copper-catalyzed enantioselective conjugate addition of organometallic reagents to challenging Michael acceptors

• Delphine Pichon,
• Jennifer Morvan,
• Christophe Crévisy and
• Marc Mauduit

Beilstein J. Org. Chem. 2020, 16, 212–232, doi:10.3762/bjoc.16.24

• reagents was reported by Alexakis and co-workers in 2010 [14]. After screening various chiral phosphine-based ligands, the combinations of either phosphoramidite L1 with Cu(OTf)2, or (R)-BINAP (L2) with copper thiophenecarboxylate (CuTC) appeared to be the most efficient for the addition of Et2Zn to a

• copper-catalyzed ECA of alkylzirconium reagents to α,β-unsaturated thioesters [33]. Starting from diversely functionalized alkenes, the resulting hydrozirconated adducts were reacted with various β-substituted Michael acceptors in the presence of CuCl and the chiral phosphoramidite L11 (Scheme 12

• addition of diethylzinc to crotonyl N-acyloxazolidinone [48]. The 1,4-product was also formed in high enantioselectivity (>98% ee) and high yield (91%). The same year, Pineschi et al. evaluated various α,β-unsaturated acyl derivatives for the copper/(R,S,S)-phosphoramidite L16-catalyzed addition of

Electrophilic oligodeoxynucleotide synthesis using dM-Dmoc for amino protection

• Shahien Shahsavari,
• Dhananjani N. A. M. Eriyagama,
• Bhaskar Halami,
• Vagarshak Begoyan,
• Marina Tanasova,
• Jinsen Chen and
• Shiyue Fang

Beilstein J. Org. Chem. 2019, 15, 1116–1128, doi:10.3762/bjoc.15.108

• removed with an acid in each synthetic cycle. The exo-amino groups of nucleosides dA, dC and dG are protected with acyl groups, the nascent ODN is anchored to a solid support via a base- or nucleophile-cleavable linker, and in the most widely used phosphoramidite technology the phosphate groups are

• electrophilic ODN synthesis technology, the phosphoramidite monomers 3a–c and the linker 4 (Figure 1) were needed. The construction of linker 4 was reported previously [40]. The synthesis of 3a–c is shown in Scheme 2. The reagent 5 needed for protecting the exo-amino groups of nucleobases was prepared in two

• steps from 1,3-dithiane (6) according to a procedure we reported previously [44]. The dC phosphoramidite monomer 3a was synthesized from compound 9 [45]. The formation of the hindered O-tert-alkyl N-arylcarbamate 10 was found highly challenging [44][46][47]. We tried many conditions and finally found

Syntheses and chemical properties of β-nicotinamide riboside and its analogues and derivatives

• Mikhail V. Makarov and
• Marie E. Migaud

Beilstein J. Org. Chem. 2019, 15, 401–430, doi:10.3762/bjoc.15.36

Synthesis, biophysical properties, and RNase H activity of 6’-difluoro[4.3.0]bicyclo-DNA

• Sibylle Frei,
• Adam K. Katolik and
• Christian J. Leumann

Beilstein J. Org. Chem. 2019, 15, 79–88, doi:10.3762/bjoc.15.9

• -DNA (6’-diF-bc4,3-DNA). The difluorinated thymidine phosphoramidite building block was synthesized starting from an already known gem-difluorinated tricyclic glycal. This tricyclic siloxydifluorocyclopropane was converted into the [4.3.0]bicyclic nucleoside via cyclopropane ring-opening through the

• addition of an electrophilic iodine during the nucleosidation step followed by reduction. The gem-difluorinated bicyclic nucleoside was then converted into the corresponding phosphoramidite building block which was incorporated into oligonucleotides. Thermal denaturation experiments of these

• analog by RNase H. In addition, the RNase H experiment was also performed with the previously report 6’F-bc4,3-DNA (Figure 1) [37]. Results and Discussion Synthesis of the phosphoramidite building block In the literature there exist several procedures to construct an α,α-difluoroketone from a

6’-Fluoro[4.3.0]bicyclo nucleic acid: synthesis, biophysical properties and molecular dynamics simulations

• Sibylle Frei,
• Andrei Istrate and
• Christian J. Leumann

Beilstein J. Org. Chem. 2018, 14, 3088–3097, doi:10.3762/bjoc.14.288

• unsaturated 6’-fluoro[4.3.0]bicyclo nucleotides (6’F-bc4,3-DNA). Two 6’F-bc4,3 phosphoramidite building blocks (T and C) were synthesized starting from a previously described [3.3.0]bicyclic sugar. The conversion of this sugar to a gem-difluorinated tricyclic intermediate via difluorocarbene addition followed

• phosphoramidite building blocks into oligonucleotides was achieved with tert-butyl hydroperoxide as oxidation agent. Thermal melting experiments of the modified duplexes disclosed a destabilizing effect versus DNA and RNA complements, but with a lesser degree of destabilization versus complementary DNA (ΔTm/mod

• duplexes. Results and Discussion Synthesis of the phosphoramidite building blocks Our strategy for the construction of the two phosphoramidite building blocks 10 and 16 envisaged as a key step the formation of a [4.3.0]bicyclic fluoroenone from a tricyclic siloxydifluorocyclopropane through a ring

Hydroarylations by cobalt-catalyzed C–H activation

• Rajagopal Santhoshkumar and
• Chien-Hong Cheng

Beilstein J. Org. Chem. 2018, 14, 2266–2288, doi:10.3762/bjoc.14.202

• the presence of Co(acac)3 and phosphoramidite ligand L afforded alkylated products 33 in high yields and enantioselectivity. A wide range of indoles and styrenes were well tolerated to form the corresponding alkyl products 33 in a branched selective manner. In addition to the directing group

Artificial bioconjugates with naturally occurring linkages: the use of phosphodiester

• Takao Shoji,
• Hiroki Fukutomi,
• Yohei Okada and
• Kazuhiro Chiba

Beilstein J. Org. Chem. 2018, 14, 1946–1955, doi:10.3762/bjoc.14.169

• activated 5’-terminus without difficulty (Scheme S2, Supporting Information File 1). Furthermore, to our delight, the conjugation was compatible with carboxylic acids that are potential nucleophiles for the activated 5’-terminus and can also induce side reactions of the phosphoramidite (Scheme 1). This